Evening administration of long-acting muscarinic antagonists in COPD - a randomized controlled trial

Pradeesh Sivapalan; Valdemar Rømer; Alexander Jordan; Niklas Dyrby Johansen; Manan Pareek; Daniel Modin; Alexander G Mathioudakis; Jørgen Vestbo; Anna Kubel Vognsen; Josefin Eklöf; John R Hurst; Tobias Wirenfeldt Klausen; Tor Biering-Sørensen; Jens-Ulrik Staehr Jensen

doi:10.1186/s12890-025-03952-y

Evening administration of long-acting muscarinic antagonists in COPD - a randomized controlled trial

Pradeesh Sivapalan^*, Valdemar Rømer, Alexander Jordan, Niklas Dyrby Johansen, Manan Pareek, Daniel Modin, Alexander G Mathioudakis, Jørgen Vestbo, Anna Kubel Vognsen, Josefin Eklöf, John R Hurst, Tobias Wirenfeldt Klausen, Tor Biering-Sørensen, Jens-Ulrik Staehr Jensen

^*Corresponding author for this work

Abstract

BACKGROUND: Night-time parasympathetic activation, diminished effect of long-acting muscarinic antagonists (LAMA) closer to end of the dosing period, and frequent exacerbations in chronic obstructive pulmonary disease (COPD) during night suggests greater benefits of evening administration of once-daily LAMA.

METHODS: We electronically invited 172,852 Danish COPD patients who used once-daily LAMA (including dual/triple therapy) to participate in a randomized controlled, digital platform, pragmatic trial comparing evening with morning LAMA administration. Of these, 10,011 patients consented and were randomized. National health registries were the main source for follow-up data. The primary endpoint was a composite of COPD exacerbations requiring hospitalization or all-cause death within one year. Secondary endpoints were moderate COPD exacerbations, all-cause hospitalization, intensive-care admission, non-invasive ventilation, all-cause mortality, and consumption of short-acting beta-2-agonists.

RESULTS: A total of 10,011 COPD patients were randomized to evening (n=4,983) or morning (n=5,028) LAMA administration. We had complete (100%) follow-up on the primary and secondary outcomes. In the evening-LAMA group, 245 persons (5%) met the primary outcome compared with 249 persons (5%) in the morning-LAMA group (P=0.93). There were 61 (1%) intensive-care admissions in the evening-LAMA group versus 95 (2%) in the morning-LAMA group (P=0.046). Other secondary outcomes were neutral. Administration-time adherence was low in the evening-LAMA group being 73% at 6 months and 66% at 12 months among survey responders (65% and 63%, respectively).

CONCLUSIONS: Evening administration of LAMA did not reduce the incidence of COPD exacerbations requiring hospitalization or all-cause death. Poor adherence may have contributed to the negative study outcome. The trial serves as a proof-of-concept for decentralized digital trials.

TRIAL REGISTRATION: Clinicaltrials.gov: NCT05563675, registered 28/09/2022 https://clinicaltrials.gov/study/NCT0556367 .

Original language	English
Article number	552
Journal	BMC Pulmonary Medicine
Volume	25
Issue number	1
Pages (from-to)	552
ISSN	1471-2466
DOIs	https://doi.org/10.1186/s12890-025-03952-y
Publication status	Published - 3 Dec 2025

Keywords

Humans
Pulmonary Disease, Chronic Obstructive/drug therapy
Muscarinic Antagonists/administration & dosage
Male
Female
Aged
Middle Aged
Denmark
Hospitalization/statistics & numerical data
Drug Administration Schedule
Disease Progression
Adrenergic beta-2 Receptor Agonists/therapeutic use
Randomized controlled trial
Circadian variation
Long-acting muscarinic antagonists (LAMA)
COPD

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Sivapalan, P., Rømer, V., Jordan, A., Johansen, N. D., Pareek, M., Modin, D., Mathioudakis, A. G., Vestbo, J., Vognsen, A. K., Eklöf, J., Hurst, J. R., Klausen, T. W., Biering-Sørensen, T., & Jensen, J.-U. S. (2025). Evening administration of long-acting muscarinic antagonists in COPD - a randomized controlled trial. BMC Pulmonary Medicine, 25(1), 552. Article 552. https://doi.org/10.1186/s12890-025-03952-y

Sivapalan, P, Rømer, V, Jordan, A , Johansen, ND , Pareek, M , Modin, D, Mathioudakis, AG, Vestbo, J, Vognsen, AK, Eklöf, J, Hurst, JR, Klausen, TW, Biering-Sørensen, T & Jensen, J-US 2025, 'Evening administration of long-acting muscarinic antagonists in COPD - a randomized controlled trial', BMC Pulmonary Medicine, vol. 25, no. 1, 552, pp. 552. https://doi.org/10.1186/s12890-025-03952-y

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title = "Evening administration of long-acting muscarinic antagonists in COPD - a randomized controlled trial",

abstract = "BACKGROUND: Night-time parasympathetic activation, diminished effect of long-acting muscarinic antagonists (LAMA) closer to end of the dosing period, and frequent exacerbations in chronic obstructive pulmonary disease (COPD) during night suggests greater benefits of evening administration of once-daily LAMA.METHODS: We electronically invited 172,852 Danish COPD patients who used once-daily LAMA (including dual/triple therapy) to participate in a randomized controlled, digital platform, pragmatic trial comparing evening with morning LAMA administration. Of these, 10,011 patients consented and were randomized. National health registries were the main source for follow-up data. The primary endpoint was a composite of COPD exacerbations requiring hospitalization or all-cause death within one year. Secondary endpoints were moderate COPD exacerbations, all-cause hospitalization, intensive-care admission, non-invasive ventilation, all-cause mortality, and consumption of short-acting beta-2-agonists.RESULTS: A total of 10,011 COPD patients were randomized to evening (n=4,983) or morning (n=5,028) LAMA administration. We had complete (100\%) follow-up on the primary and secondary outcomes. In the evening-LAMA group, 245 persons (5\%) met the primary outcome compared with 249 persons (5\%) in the morning-LAMA group (P=0.93). There were 61 (1\%) intensive-care admissions in the evening-LAMA group versus 95 (2\%) in the morning-LAMA group (P=0.046). Other secondary outcomes were neutral. Administration-time adherence was low in the evening-LAMA group being 73\% at 6 months and 66\% at 12 months among survey responders (65\% and 63\%, respectively).CONCLUSIONS: Evening administration of LAMA did not reduce the incidence of COPD exacerbations requiring hospitalization or all-cause death. Poor adherence may have contributed to the negative study outcome. The trial serves as a proof-of-concept for decentralized digital trials.TRIAL REGISTRATION: Clinicaltrials.gov: NCT05563675, registered 28/09/2022 https://clinicaltrials.gov/study/NCT0556367 .",

keywords = "Humans, Pulmonary Disease, Chronic Obstructive/drug therapy, Muscarinic Antagonists/administration \& dosage, Male, Female, Aged, Middle Aged, Denmark, Hospitalization/statistics \& numerical data, Drug Administration Schedule, Disease Progression, Adrenergic beta-2 Receptor Agonists/therapeutic use, Randomized controlled trial, Circadian variation, Long-acting muscarinic antagonists (LAMA), COPD",

author = "Pradeesh Sivapalan and Valdemar R{\o}mer and Alexander Jordan and Johansen, \{Niklas Dyrby\} and Manan Pareek and Daniel Modin and Mathioudakis, \{Alexander G\} and J{\o}rgen Vestbo and Vognsen, \{Anna Kubel\} and Josefin Ekl{\"o}f and Hurst, \{John R\} and Klausen, \{Tobias Wirenfeldt\} and Tor Biering-S{\o}rensen and Jensen, \{Jens-Ulrik Staehr\}",

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = dec,

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doi = "10.1186/s12890-025-03952-y",

language = "English",

volume = "25",

pages = "552",

journal = "BMC Pulmonary Medicine",

issn = "1471-2466",

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TY - JOUR

T1 - Evening administration of long-acting muscarinic antagonists in COPD - a randomized controlled trial

AU - Sivapalan, Pradeesh

AU - Rømer, Valdemar

AU - Jordan, Alexander

AU - Johansen, Niklas Dyrby

AU - Pareek, Manan

AU - Modin, Daniel

AU - Mathioudakis, Alexander G

AU - Vestbo, Jørgen

AU - Vognsen, Anna Kubel

AU - Eklöf, Josefin

AU - Hurst, John R

AU - Klausen, Tobias Wirenfeldt

AU - Biering-Sørensen, Tor

AU - Jensen, Jens-Ulrik Staehr

PY - 2025/12/3

Y1 - 2025/12/3

N2 - BACKGROUND: Night-time parasympathetic activation, diminished effect of long-acting muscarinic antagonists (LAMA) closer to end of the dosing period, and frequent exacerbations in chronic obstructive pulmonary disease (COPD) during night suggests greater benefits of evening administration of once-daily LAMA.METHODS: We electronically invited 172,852 Danish COPD patients who used once-daily LAMA (including dual/triple therapy) to participate in a randomized controlled, digital platform, pragmatic trial comparing evening with morning LAMA administration. Of these, 10,011 patients consented and were randomized. National health registries were the main source for follow-up data. The primary endpoint was a composite of COPD exacerbations requiring hospitalization or all-cause death within one year. Secondary endpoints were moderate COPD exacerbations, all-cause hospitalization, intensive-care admission, non-invasive ventilation, all-cause mortality, and consumption of short-acting beta-2-agonists.RESULTS: A total of 10,011 COPD patients were randomized to evening (n=4,983) or morning (n=5,028) LAMA administration. We had complete (100%) follow-up on the primary and secondary outcomes. In the evening-LAMA group, 245 persons (5%) met the primary outcome compared with 249 persons (5%) in the morning-LAMA group (P=0.93). There were 61 (1%) intensive-care admissions in the evening-LAMA group versus 95 (2%) in the morning-LAMA group (P=0.046). Other secondary outcomes were neutral. Administration-time adherence was low in the evening-LAMA group being 73% at 6 months and 66% at 12 months among survey responders (65% and 63%, respectively).CONCLUSIONS: Evening administration of LAMA did not reduce the incidence of COPD exacerbations requiring hospitalization or all-cause death. Poor adherence may have contributed to the negative study outcome. The trial serves as a proof-of-concept for decentralized digital trials.TRIAL REGISTRATION: Clinicaltrials.gov: NCT05563675, registered 28/09/2022 https://clinicaltrials.gov/study/NCT0556367 .

AB - BACKGROUND: Night-time parasympathetic activation, diminished effect of long-acting muscarinic antagonists (LAMA) closer to end of the dosing period, and frequent exacerbations in chronic obstructive pulmonary disease (COPD) during night suggests greater benefits of evening administration of once-daily LAMA.METHODS: We electronically invited 172,852 Danish COPD patients who used once-daily LAMA (including dual/triple therapy) to participate in a randomized controlled, digital platform, pragmatic trial comparing evening with morning LAMA administration. Of these, 10,011 patients consented and were randomized. National health registries were the main source for follow-up data. The primary endpoint was a composite of COPD exacerbations requiring hospitalization or all-cause death within one year. Secondary endpoints were moderate COPD exacerbations, all-cause hospitalization, intensive-care admission, non-invasive ventilation, all-cause mortality, and consumption of short-acting beta-2-agonists.RESULTS: A total of 10,011 COPD patients were randomized to evening (n=4,983) or morning (n=5,028) LAMA administration. We had complete (100%) follow-up on the primary and secondary outcomes. In the evening-LAMA group, 245 persons (5%) met the primary outcome compared with 249 persons (5%) in the morning-LAMA group (P=0.93). There were 61 (1%) intensive-care admissions in the evening-LAMA group versus 95 (2%) in the morning-LAMA group (P=0.046). Other secondary outcomes were neutral. Administration-time adherence was low in the evening-LAMA group being 73% at 6 months and 66% at 12 months among survey responders (65% and 63%, respectively).CONCLUSIONS: Evening administration of LAMA did not reduce the incidence of COPD exacerbations requiring hospitalization or all-cause death. Poor adherence may have contributed to the negative study outcome. The trial serves as a proof-of-concept for decentralized digital trials.TRIAL REGISTRATION: Clinicaltrials.gov: NCT05563675, registered 28/09/2022 https://clinicaltrials.gov/study/NCT0556367 .

KW - Humans

KW - Pulmonary Disease, Chronic Obstructive/drug therapy

KW - Muscarinic Antagonists/administration & dosage

KW - Male

KW - Female

KW - Aged

KW - Middle Aged

KW - Denmark

KW - Hospitalization/statistics & numerical data

KW - Drug Administration Schedule

KW - Disease Progression

KW - Adrenergic beta-2 Receptor Agonists/therapeutic use

KW - Randomized controlled trial

KW - Circadian variation

KW - Long-acting muscarinic antagonists (LAMA)

KW - COPD

UR - https://www.scopus.com/pages/publications/105023768335

U2 - 10.1186/s12890-025-03952-y

DO - 10.1186/s12890-025-03952-y

M3 - Journal article

C2 - 41340061

SN - 1471-2466

VL - 25

SP - 552

JO - BMC Pulmonary Medicine

JF - BMC Pulmonary Medicine

IS - 1

M1 - 552

ER -

Evening administration of long-acting muscarinic antagonists in COPD - a randomized controlled trial

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